Abstract

Here we report corin, a synthetic hybrid agent derived from the class I HDAC inhibitor (entinostat) and an LSD1 inhibitor (tranylcypromine analog). Enzymologic analysis reveals that corin potently targets the CoREST complex and shows more sustained inhibition of CoREST complex HDAC activity compared with entinostat. Cell-based experiments demonstrate that corin exhibits a superior anti-proliferative profile against several melanoma lines and cutaneous squamous cell carcinoma lines compared to its parent monofunctional inhibitors but is less toxic to melanocytes and keratinocytes. CoREST knockdown, gene expression, and ChIP studies suggest that corin's favorable pharmacologic effects may rely on an intact CoREST complex. Corin was also effective in slowing tumor growth in a melanoma mouse xenograft model. These studies highlight the promise of a new class of two-pronged hybrid agents that may show preferential targeting of particular epigenetic regulatory complexes and offer unique therapeutic opportunities.

Dual inhibitors exhibit unique activity against the CoREST complex. a Coomassie stained gel depicting the three components of the CoREST ternary complex after purification by size exclusion chromatography. b Dose response produced by inhibition of LSD1 as part of the CoREST complex by corin and structurally matched compound 7. c Inhibition curves generated for corin and MS-275 against HDAC1 as part of the CoREST complex. d Corin inhibited the deacetylation of reconstituted nucleosomes by the CoREST complex as determined by Western blot (CoREST complex = 100 nM, nucleosome = 100 nM). Data (mean ± SEM) are representative of at least two independent experiments